The known risk factors for breast cancer - environmental, behavioral and genetic - account only for about 25% of the variability in incidence. Investigations of the interplay of genes and environment are needed to elucidate the pathogenesis of the disease. The purpose of the proposed research is to 1) determine the morbidity and mortality status of an established cohort of first- and second-degree female relatives (sisters, daughters, nieces, granddaughters) of a group of breast cancer probands originally studied at the University of Minnesota between 1944 and 1952; 2) to examine how epidemiologic risk factors influence lifetime cumulative risk by performing segregation analyses that incorporate environmental/behavioral covariates (including parenchymal pattern) using breast cancer and some or all subtypes of benign breast disease as phenotypes; 3) to explore the genetic heterogeneity of breast cancer in subsets of families defined by both the types of malignancies observed and histologic type of the proband (determined by a review of the pathology slides from the original cohort); 4) to perform genetic linkage analyses on a subset of informative families using a candidate gene approach to confirm the existence of a susceptibility gene(s). Detailed, documented histories of breast and other cancers are known for both maternal and paternal blood lines. These data are noteworthy for several reasons: 1) the sampling scheme at baseline was population-based and is easily allowed for in the analyses; 2) the number of generations with complete cancer histories minimizes the uncertainty of inherited susceptibility to diseases with variable age at onset; 3) the large number of families permits exploration of genetic heterogeneity of breast cancer and minimizes the misclassification of families as sporadic, familial or hereditary; and 4) a number of medical history/reproductive risk factors were collected on these relatives at baseline. Using established tracking procedures, we will update the vital status of family members and extend the pedigrees to include grandchildren. We have already successfully located at least one family member in all of the families selected for the pilot study. Questionnaire data, mammographies and blood samples will be obtained. Outcomes of the analysis will include a quantitative risk of breast cancer attributable to a family history; information on the pattern of inheritance of susceptibility to breast and other cancers; and evidence to support the physical location of a susceptibility gene(s). The proposed project will provide valuable information on the genetic epidemiology of breast cancer vital to primary prevention of the disease.